Monoterpenes are a class of phytochemicals that possess cancer preventative and therapeutic properties. The prototypical monoterpene Perillyl alcohol (POH) is currently in clinical trials for the treatment of cancers. In spite of their promise of monoterpenes as anticancer agents, a lack of understanding of their mechanism of action has hampered their development in cancer prevention and control. We recently identified the transcriptional regulator, GADD153, as a potential biomarker for monoterpene action. GADD153 is thought to control growth arrest and apoptosis in response to certain types of cellular stress. It is anticipated that monitoring GADD153 expression will allow rapid and quantitative assessment of monoterpene activity. We have also identified the glutathione (GSH) pathway as the molecular target of monoterpenes. A strong correlation (r-value approximately 0.9) was observed between amount of decrease in GSH levels and the potency (ID50) for growth suppression by a various monoterpenes indicating that these two events are linked. Specific Aim 1 will determine whether GADD153 is a useful marker of monoterpene action for differential cell sensitivity between normal cells and various tumor cell types. Specific Aim 2 will determine the mechanism(s) by which monoterpenes deplete GSH. Specific Aim 3 will examine the possibility that depletion of cellular GSH by monoterpenes will sensitize tumor cells to chemotherapy with particular emphasis place on agents that are susceptible to resistance through modulation of the GSH pathways. By understanding the mechanism of action of monoterpenes and having a useful marker of its activity it should be possible to define more effective monoterpenes for cancer prevention and therapy, monitor therapeutic responsiveness, determine which types of cancer might be more responsive to monoterpene therapy, and identify which chemotherapeutic agents may be augmented by monoterpene adjuvant therapy.